Contraindications and Drug Interactions

11.3 Other Pharmacotherapies

11.3.1 Varenicline

Nicotine฀receptor฀partial฀agonists฀such฀as฀varenicline฀may฀help฀to฀stop฀smoking฀by฀reduc- ing฀smoking฀satisfaction฀acting฀as฀an฀antagonist฀and฀also฀maintaining฀moderate฀levels฀of฀ dopamine฀to฀counteract฀withdrawal฀symptoms฀acting฀as฀an฀agonist.฀In฀this฀respect,฀varen- icline฀was฀developed฀as฀a฀nicotine฀receptor฀partial฀agonist฀from฀cytosine.฀It฀is฀a฀drug฀that฀is฀ widely฀used฀in฀Central฀and฀Eastern฀Europe฀for฀smoking฀cessation.฀The฀irst฀trial฀reports฀of฀ varenicline฀were฀released฀in฀2006,฀and฀further฀trials฀have฀now฀been฀published฀or฀are฀cur- rently฀are฀underway.฀A฀Cochrane฀analysis฀published฀in฀2008฀assessed฀the฀eficacy฀and฀tol- erability฀of฀nicotine฀receptor฀partial฀agonists,฀including฀varenicline฀and฀cytisine฀for฀smoking฀ cessation฀ [121] .฀Together฀with฀other฀databases฀the฀Cochrane฀Tobacco฀Addiction฀Group’s฀ specialised฀register฀for฀trials฀was฀searched฀and฀randomized฀controlled฀trials฀which฀com- pared฀the฀treatment฀drug฀with฀placebo฀were฀analysed.฀Comparisons฀with฀bupropion฀and฀ NRT฀were฀also฀performed.฀Seven฀trials฀of฀varenicline฀compared฀with฀placebo฀for฀smoking฀ cessation฀were฀found;฀three฀of฀these฀also฀included฀a฀bupropion฀experimental฀arm.฀Also฀one฀ relapse฀prevention฀trial,฀comparing฀varenicline฀with฀placebo,฀and฀one฀open-label฀trial฀com- paring฀varenicline฀with฀NRT฀were฀identiied฀ [121] .฀In฀total,฀the฀nine฀trials฀covered฀7,267฀ participants,฀4,744฀of฀whom฀used฀varenicline.฀As฀a฀result,฀the฀pooled฀risk฀ratio฀RR฀for฀ continuous฀abstinence฀at฀6฀months฀or฀longer฀for฀varenicline฀vs.placebo฀was฀2.33฀95฀CI฀ 1.95–2.80.฀ The฀ pooled฀ RR฀ for฀ varenicline฀ vs.bupropion฀ at฀ 1฀ year฀ was฀ 1.52฀ 95฀ CI฀฀ 1.22–1.88.฀The฀RR฀for฀varenicline฀vs.NRT฀at฀1฀year฀was฀1.31฀95฀CI฀1.01–1.71.฀The฀ two฀trials฀which฀tested฀the฀use฀of฀varenicline฀beyond฀the฀12-week฀standard฀regimen฀found฀ the฀drug฀to฀be฀well-tolerated฀during฀long-term฀use.฀The฀main฀adverse฀effect฀of฀varenicline฀ was฀nausea,฀which฀was฀mostly฀at฀mild฀to฀moderate฀levels฀and฀usually฀subsided฀over฀time฀ [121] .฀Post-marketing฀safety฀data฀suggest฀that฀varenicline฀may฀be฀associated฀with฀depressed฀ mood,฀agitation,฀and฀suicidal฀behaviour฀or฀ideation.฀The฀labelling฀of฀varenicline฀has฀been฀ amended,฀and฀the฀FDA฀is฀conducting฀a฀safety฀review.The฀one฀cytisine฀trial฀included฀in฀this฀ Cochrane฀review฀found฀that฀more฀participants฀taking฀cytisine฀stopped฀smoking฀compared฀ with฀placebo฀at฀2฀years฀follow฀up,฀with฀an฀RR฀of฀1.61฀95฀CI฀1.24–2.08. It฀can฀be฀concluded฀from฀this฀Cochrane฀analysis฀that฀varenicline฀increases฀the฀chances฀ of฀successful฀long-term฀smoking฀cessation฀between฀two-฀and฀threefold฀compared฀with฀ pharmacologically฀ unassisted฀ quit฀ attempts.฀ Also,฀ more฀ participants฀ quit฀ successfully฀ with฀varenicline฀than฀with฀bupropion.฀The฀one฀analysed฀open-label฀trial฀of฀varenicline฀vs.฀ NRT฀demonstrated฀a฀modest฀beneit฀of฀varenicline.฀The฀main฀adverse฀effect฀of฀varenicline฀ is฀nausea,฀but฀mostly฀at฀mild฀to฀moderate฀levels฀and฀tending฀to฀subside฀over฀time.฀Possible฀ links฀with฀serious฀AEs,฀including฀depressed฀mood,฀agitation฀and฀suicidal฀thoughts,฀are฀ currently฀ under฀ review.฀ It฀ can฀ be฀ stated฀ that฀ there฀ is฀ a฀ need฀ for฀ larger,฀ independent฀฀ community-based฀trials฀of฀varenicline฀to฀test฀the฀eficacy฀of฀treatment฀extended฀beyond฀ 12฀weeks฀ [121] .